Rationale for the treatment of cancer with sodium selenite

Epidemiological studies conducted during several decades of the last century have demonstrated the importance of sufficient nutritional supply of selenium (Se) for human health. More importantly, low blood Se levels were found to be associated with an increased incidence and mortality from various types of cancers. Recently, attention of researchers was drawn to the relationship between free radical generation, known otherwise as oxidative stress, and carcinogenesis. It was therefore thought that antioxidants should be beneficial for prevention and inhibition of different malignancies. However, there appeared to be a paradox, because tumor growth is associated with tissue hypoxia that is accompanied by the formation of reductive rather than oxidative free radicals. Various organic and inorganic Se compounds, generally considered to be antioxidants, produced mixed results when tested in animal models and human subjects. Amongst them, sodium selenite has been shown to be the most effective in an in vitro and in vivo carcinogenesis studies. As recently demonstrated, selenite is not an antioxidant, but possesses oxidizing properties in the presence of specific substrates. Thus selenite is capable of oxidizing polythiols to corresponding disulfides, but does not react with monothiols. Such polythiols associated with cancer membrane-bound proteins appear under the reducing conditions of hypoxic tumor tissue. These thiol groups can, in turn, initiate a disulfide exchange reaction with plasma proteins, predominantly with fibrinogen, to form an insoluble and protease-resistant fibrin-like polymer. As the result, tumor cells become surrounded by a coat which masks specific tumor antigens thus allowing cancer cells to escape immune recognition and elimination by natural killer (NK) cells. Selenite by virtue of oxidizing cell membrane thiols, can prevent the formation of the coat and consequently makes cancer cells vulnerable to the immune surveillance and destruction. In addition, selenite may directly activate NK cells, as well as inhibit angiogenesis without undesirable decrease in the oxidative potential of cellular environment. It is, therefore, postulated that sodium selenite, in view of its relative low toxicity, might become a drug of choice for many types of cancer including leukemia.     

Clinical decision-support for diagnosing stress-related disorders by applying psychophysiological medical knowledge to an instance-based learning system

OBJECTIVE: An important procedure in diagnosing stress-related disorders caused by dysfunction in the interaction of the heart with breathing, i.e., respiratory sinus arrhythmia (RSA), is to analyse the breathing first and then the heart rate. Analysing these measurements is a time-consuming task for the diagnosing clinician. A decision-support system in this area would reduce the analysis task of the clinician and enable him/her to give more attention to the patient. We have created a decision-support system which contains a signal classifier and a pattern identifier. The system performs an analysis of the physiological time series concerned which would otherwise be performed manually by the clinician. METHODS: The signal-classifier, HR3Modul, classifies heart-rate patterns by analysing both cardio- and pulmonary signals, i.e., physiological time series. HR3Modul uses case-based reasoning (CBR), using a wavelet-based method for retrieving features from the signals. The system searches for familiar shapes in the signals by comparing them with shapes already stored. We have applied a best fit scheme for handling signals of different lengths, as the length of a breath is highly dynamic. We also apply automatic weighting to the features to obtain a more autonomous system. The classified heart signals indicate if a patient may be suffering from a stress-related disorder and the nature of the disorder. These classified signals are thereafter sent to the second subsystem, the pattern-identifier. The pattern-identifier analyses the classified signals and searches for familiar patterns by identifying sequences in the classified signals. The identified sequences give clinicians a more complete analysis of the measurements, providing them with a better basis for diagnosis. RESULTS AND CONCLUSION: We have shown that a case-based classifier with a wavelet feature extractor and automatic weighting is a viable option for building a decision-support system for the psychophysiological domain, as it is at par, or even outperforms other retrieval techniques and is less complex.     

Quantified deficiency of lymphocyte response to phytohaemagglutinin in immune deficiency diseases

Using a quantitative assay of lymphocyte responsiveness to different concentrations of phytohaemagglutinin (PHA), it has been possible to demonstrate that the lymphocytes of children with ataxia telangiectasia do not respond normally. The response to PHA is nearer normal at higher concentrations of PHA.

In the same system, it has been shown that although the lymphocytes of children with probable infantile sex-linked agammaglobulinaemia (Bruton's disease) may respond normally at higher concentrations of PHA, at lower concentrations their response is subnormal.

The results reported indicate that if lymphocyte response to PHA is defective in an immune deficiency disease, then the response at lower concentrations of PHA provides the most sensitive discriminatory information.

     

Beta-lactams in sexually transmitted diseases: Rationale for selection and dosing regimens

A review is given of the selection and rationale of optimal treatment regimens for patients with sexually transmitted pathogens, e.g. in cases of gonorrhea, chlamydial infections, chancroid, syphilis, pelvic inflammatory diseases and ophthalmia neonatorum. The scientific basis for the selection of a beta-lactam agent is discussed, including dose, MIC, the critical serum level and maintenance interval, and the duration of therapy. Except in the case of penicillinase-producingNeiserria gonorrhoeae, penicillin remained until recently the most effective agent available against many sexually transmitted diseases. However, ceftriaxone, a new third-generation cephalosporin, has been shown to have a long half-life (8 h) and excellent in vitro efficacy againstNeiserria gonorrhoeae (including penicillinase-producing strains) andHaemophilis ducreyi. In view of its exceptional clinical efficacy against both gonorrhea and chancroid, clinical studies of its efficacy against other sexually transmitted diseases appear warranted.     

Allogeneic stem cell transplantation for the treatment of diseases associated with a deficiency in bone marrow products

Our understanding of the pathophysiology of hematopoietic failure associated syndromes led to the developmental of potentially curative procedures for the treatment of many diseases including Severe aplastic anemia, Fanconis anemia, Primary immunodeficiency, Osteopetrosis, and Metabolic diseases. Although the number of patients that were transplanted for bone marrow deficiency diseases is relatively low as compared to patients with hematological malignancies, the impact on the knowledge of hematopoiesis and transplantation biology is tremendous. Moreover, the patients average young age suffering from these diseases further encourage searching for curative approaches. Lucking a fully MHC matched donor, remained a significant obstacle in stem cell transplantation for non-malignant hematological disorders. Lessons from attempts to cure aplasic anemia with bone marrow transplantation guided us to the improvement of pretransplant conditioning regimens and prevention of graft versus host reactions after transplantation. Furthermore, in recent years optimization of disease specific protocol have been successfully designed and clinically applied.     

Specific response to adrenaline in arterial hypertension induced by exogenous calcium deficiency

Injection of a synthetic analog of parathyroid hypertensive factor to WKY rats considerably increases and prolongs pressor response to adrenaline. Synthetic analog injected after adrenaline induces a short-term (3–4 min) and potent (to 250%) rise of arterial pressure. Each subsequent injection of the synthetic analog induces a less pronounced in the amplitude and duration pressor response. The α-adrenoblocker phentolamine completely abolishes the effects of the parathyroid hypertensive factor analog. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 8, pp. 148–150, August, 1997     

Hemiglobin-iron for the prophylaxis and treatment of iron deficiency

Summary Many natural chelators within the diet react with inorganic iron and reduce considerably its bioavailability also from therapeutic doses so that an effective oral treatment with inorganic iron preparations has to be administered on the empty stomach, without meals, tea, coffee, milk etc. Hemiglobin iron, in contrast, cannot react with iron chelators because of its stable binding in the heme moiety and does not lose its full bioavailability if administered together or within meals or beverages. The gastrointestinal side effects which are produced by the available ferrous iron of inorganic iron preparations in at least 4–7% of the subjects receiving 2×50=100 mg Fe²⁺/day have not been observed when using hemiglobin iron.The dose-relationship of hemiglobin iron bioavailability has been measured by whole body counting in subjects with normal and depleted iron stores and used for calculating hemiglobin iron doseschedules for the prevention and treatment of different grades of iron deficiency. Because of the considerable reduction of the proportion of absorbed iron which occurs when hemiglobin iron doses are increased to 20 and 50 mg iron equivalents respectively, single oral doses should not contain more than 10 mg hemiglobin iron in subjects with normal iron stores and not more than 20 mg hemiglobin iron in subjects with depleted iron stores.The daily iron deficit of 0.6 mg in females with average menstrual blood losses can be covered by 5 mg hemiglobin iron per day whereas two daily doses of 5 mg hemiglobin iron can compensate upper normal limit menstrual blood losses and would be sufficient to prevent the development of iron deficiency anemia in pregnant women. Blood losses of up to 10 ml/day in subjects with normal iron stores and up to 18 ml/day in subjects with depleted iron stores can be compensated by a maintenance therapy with 4-times 10 to 20 mg hemiglobin iron per day. Blood losses of more than 20 ml per day (up to 150 ml blood/day) do require ferrous iron therapy because of its higher bioavailability at the 50 mg Fe dose level.Exhausted iron stores can be repleted either within 120 days with 4-times 10 mg hemiglobin iron/day or in 133 day with 50 mg Fe²⁺/day. Because of the different dose relationship values larger hemiglobin iron (>20 mg) doses are less effectively absorbed than comparable ferrous iron doses. Longer periods of treatment and larger total doses are therefore required for the medication in patients with severe iron deficiency anemia.Supported in part by research grants of the Deutsche Forschungsgemeinschaft     

Possible treatment of some genetic deficiency diseases — A hypothesis

A conceptual hypothesis for the possibility of treatment of genetic deficiency diseases utilizing genetic engineering techniques is presented. It is proposed that the gene responsible for the synthesis of a protein which is missing in the patient may be inserted into the patient's stem cells using already established techniques of gene splicing and delivery. The so modified stem cells, if put back into the patient's system (e.g. bone marrow), by virtue of their ability of self multiplication are likely to start synthesizing and continue to produce missing protein. Since stem cells are also capable of differentiating into various blood cells, the nucleated blood cells are also likely to begin production of the protein whose gene was inserted into the stem cells. In this way a blood protein synthesized by any organ (e.g. liver) in normal persons may be synthesized by stem cells or their differentiated forms in the patient resulting in correction of the deficiency. Certain genetically deficient animals may be used to prove this hypothesis.     

Cost-effectiveness of genome sequencing for diagnosing patients with undiagnosed rare genetic diseases

PurposeTo estimate the cost-effectiveness of genome sequencing (GS) for diagnosing critically ill infants and noncritically ill pediatric patients (children) with suspected rare genetic diseases from a United States health sector perspective.MethodsA decision-analytic model was developed to simulate the diagnostic trajectory of patients. Parameter estimates were derived from a targeted literature review and meta-analysis. The model simulated clinical and economic outcomes associated with 3 diagnostic pathways: (1) standard diagnostic care, (2) GS, and (3) standard diagnostic care followed by GS.ResultsFor children, costs of GS ($7284) were similar to that of standard care ($7355) and lower than that of standard care followed by GS pathways ($12,030). In critically ill infants, when cost estimates were based on the length of stay in the neonatal intensive care unit, the lowest cost pathway was GS ($209,472). When only diagnostic test costs were included, the cost per diagnosis was $17,940 for standard, $17,019 for GS, and $20,255 for standard care followed by GS.ConclusionThe results of this economic model suggest that GS may be cost neutral or possibly cost saving as a first line diagnostic tool for children and critically ill infants.     

中国人重要遗传病临床实践指南专辑导读

随着新一代测序技术(next-generation sequencing,NGS)在人类遗传病研究和临床应用中的推广,遗传检测在遗传性疾病临床诊断上的作用和需求更为突出,遗传变异的信息解读也面临更多的挑战。临床上如何针对疾病对象选择合理的检测方法,如何正确解读实验室发出的基因型检测报告,并依据遗传检测结果与临床表型的关系准确诊断遗传病,是临床上广受关注的核心问题,也是目前在我国医院体系中还没有设立独立医学遗传学专科的背景下,本学科所面临的重要任务。     

MRCP在常见胰腺病变中的应用价值研究

目的:探讨MRCP对常见胰腺病变诊断的准确性及其对治疗的指导作用。方法:采用扫描序列包括冠状位T2WI、轴位T2WI、厚层和薄层MRCP,如果发现肿块,加做轴位T1WI、T1WIFS,必要时做动态增强扫描,对42例胰腺病变进行MRCP检查,观察所获得的MR图像。结果:(1)胰腺炎MRCP可见扩张的胰管沿胰腺长轴多呈不规则型或串珠样改变,而且多贯穿病变区。胰腺炎MRCP诊断的准确率为88.1%。(2)MRCP可显示典型的胰头癌的胰管和总胆管均扩张,并且没有汇合而形成的“双管征”。发生在体尾部的胰腺癌,MRCP可以显示病变处胰管中断,病变尾侧的胰管扩张。MRCP诊断胰腺癌的准确率为84.2%。结论:MRCP可以确定管腔的解剖结构而无发生并发症的危险。对确定常见的解剖变异,胰腺炎胰管的状态,肿瘤的定性,尤其是与MRI平扫及增强图像相结合时,MRCP具有很高的应用价值。